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STEM CELL THERAPY

-A REVIEW

Shefali Barkat Dobani*1, Ameesh Shukla1, Dr. Vanita Kanase2, Dr. Pramila Yadav3

1*,1

Oriental College of Pharmacy, Sector 2, Behind Sanpada Railway Station, Sanpada West,

Navi Mumbai, Maharashtra 400705.

2

HOD Pharmacology, Oriental College of Pharmacy, Sector 2, Behind Sanpada Railway

Station, Sanpada West, Navi Mumbai, Maharashtra 400705.

3

Professor in Pharmacology, Dr. D. Y. Patil Medical College, Nerul, Navi Mumbai,

Maharashtra 400614.

ABSTRACT

The regeneration of a lost tissue is known to mankind for several years.

The research on regenerative medicine has gained momentum in the

field of molecular biology. Stem cells have been successfully isolated

from variety of human tissues. Initial evidence from pioneering studies

has documented that stem cells are used for various life-threatening

diseases that have so far defeated modern medical care. The growing

understanding of biological concepts in the regeneration of human

tissues coupled with experiments on stem cells is likely to result in a

paradigm shift in the therapeutic medicines. This review focuses on the

origin of stem cells, their types, their properties, characteristics, their

potential applications, therapies for various diseases and recent

advances in the stem cell therapy.

KEYWORDS: Stem cell, pluripotent, self renewal, differentiation, stem cell therapy for diabetes, cancer, arthritis, Parkinson’s and Alzheimer’s disease.

INTRODUCTION

Stem cells are the body’s natural reservoir – replenishing stocks of specialized cells that have been used up or damaged. Inside one’s bone marrow, stem cells make 100,000 million new

blood cells one needs every single day. Stem cells have the unique ability to produce both

copies of themselves (self-renewal) and other more specialized cell types (differentiation)

every time they divide. Stem cells, therefore, are essential to the maintenance of tissues such

Volume 5, Issue 5, 437-450. Review Article ISSN 2277– 7105

*Corresponding Author Shefali Barkat Dobani Oriental College of

Pharmacy, Sector 2,

Behind Sanpada Railway

Station, Sanpada West,

Navi Mumbai,

Maharashtra 400705. Article Received on 28 Feb 2016,

Revised on 18March 2016, Accepted on 08 April 2016

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as blood, skin, and gut that undergo continuous turnover (cell replacement), and muscle,

which can be built up according to the body's needs and is often damaged during physical

exertion.Stem cells are found in the early embryo, the foetus, placenta, umbilical cord, and in

many different tissues of the body. Recently, stem cells have also been engineered from

somatic cells. They are used in the treatment of many disorders and the research in the

modification of the existing treatment of various genetic disorders is still going on.[1]

TYPES OF STEM CELLS

Various types of stem cells are observed in the human body which are classified as.

1)“TISSUE STEM CELLS” - also sometimes called adult stem cells because each type of adult stem cell produces only a limited set of specialized cells characteristic of a particular

tissue — epidermis, blood, and so on - are derived from or resident in a fetal or adult tissue.

Usually they can only give rise to the cells of that tissue. In some tissues, these cells sustain

turnover and repair throughout life. In adults, tissue-specific stem cells are located throughout

the body. The so- called hematopoetic stem cells in bone marrow and umbilical cord blood,

which make all the different types of blood cells, are the easiest to isolate, and have been

used in therapy for decades as bone marrow transplants for diseases such as leukemia, where

the normal development of blood cells has gone awry. For example, stem cells that are found

in the skin will produce new skin cells, ensuring that old or damaged skin cells are

replenished.[2]

2)“EMBRYONIC STEM CELLS”-These cells are derived from a small group of cells (called the inner cell mass) within the very early embryo. Human embryonic stem cells are

obtained from embryos that are 5-6 days old. At the stage that embryonic stem cells are

derived, the embryo is called blastocyst. Embryonic stem cells are said to be pluripotent –

they are able to form all the different types of cell in the body, including germ cells.[2]

3)“INDUCED PLURIPOTENT STEM CELLS”- Recently, a third type of stem cell, with

properties similar to embryonic stem cells, has emerged. Scientists have engineered these

induced pluripotent stem cells (iPS cells) by manipulating the expression of certain genes -

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STEM CELL BANKING

Stem cells which is obtained from cord blood can be preserved in the banks. Cord blood,

which contains powerful life saving cells called stem cells, comes from a newborn's umbilical

cord and is collected immediately after birth. Once the umbilical cord has been clamped and

cut, the remaining blood in the umbilical cord is drawn into a collection bag. It may be then

tested, frozen and subsequently stored in a cord blood bank for future use for the treatment of

various diseases. Cord blood stem cells have been successfully used in transplant medicine

for more than 20 years. Cord blood has been used to treat many life-threatening diseases

including leukemia, other cancers, blood disorders, metabolic disorders, and immune

diseases.[3]

MEDICAL USES OF STEM CELL THERAPY

Disease and conditions where stem cell treatment is promising or emerging are:[4]

 Research

 Clinical trials

 Neurodegeneration

 Brain and spinal cord injury

 Blood cell formation

 Baldness

 Missing teeth

 Deafness

 Diabetes

 Transplantation

 Orthopaedics

 Infertility

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STEM CELL BASED THERAPY

Adult stem cells have been used in pilot studies as potential cell-based therapy for various

diseases. The following stem cell characteristics make them good candidates for cell-based

therapy.

1. Potential to be harvested from patients.

2. High capacity of cell proliferation in culture.

3. Ease of manipulation to replace existing nonfunctional genes via gene splicing methods.

4. Ability to migrate to host target tissues (homing).

5. Ability to integrate into host tissues and interact with the surrounding tissues.[5]

PROCESS OF STEM CELL BASED THERAPY

Stem cells derived from either peripheral blood, cord blood, bone marrow, or any adult tissue

transported in the right medium to the laboratory is centrifuged, trypsinized, and propagated

under ideal conditions and stored in the master cell bank (MCB). The MCB is further

passaged to yield colonies of stem cells, given the right inductive signals using appropriate

growth factors to allow them to differentiate into required cell types. These are injected or

implanted into a patient as cell-based therapy. Homing will ensure that the stem cells reach

the site of injury/tissues. Today, the two common methods of cell delivery are intravenous

(5)

using a carrier). The cell encapsulation approach uses a biocompatible, biodegradable

material construct that is seeded with cells and implanted into defects in order to regenerate

the lost tissue.[5]

STEM CELL THERAPY FOR DIABETES

Diabetes mellitus (or diabetes) is a chronic, lifelong condition that affects your body's ability

to use the energy found in food. There are three major types of diabetes: type 1 diabetes, type

2 diabetes, and gestational diabetes. Curative therapy for diabetes mellitus mainly implies

replacement of functional insulin-producing pancreatic cells, with pancreas or islet-cell

transplants[6].

Stem cell therapy for diabetes implies the replacement of diseased or lost cells from progeny

of pluripotent or multipotent cells. Both embryonic stem cells (derived from the inner cell

mass of a blastocyst) and adult stem cells (found in the postnatal organism) have been used to

generate surrogate cells[6] or otherwise restore cell functioning. In isolated pancreatic tissue,

pancreas-resident progenitor cells might give rise to endocrine islet cells.

Human and rodent pancreatic-duct cells[7,8],islet-derived cells[9,10], and exocrine tissue[11]

contain cells that can differentiate towards a pancreatic endocrine phenotype. These tissues,

cultured and differentiated in vitro, have been transplanted and can reverse diabetes mellitus

in rodents. Rodent-liver stem cells and human fetal-liver cells have been differentiated in

vitro into insulin-secreting cells by culture methods and/or introduction of cell-specific genes.

When transplanted, these cells reverse diabetes mellitus in rodents[12]. Cells within liver that

can differentiate into insulin-secreting cells after introduction of ß-cell-specific genes have

also been seen in vivo after adenoviral gene-delivery into rodents that have been rescued

from diabetes for long periods[13,14].

A bone-fide pancreatic stem cell for cell regeneration remains elusive. A genetic-marking

study in mice casts doubt on the existence of any cell progenitor cells and suggests that cells

regenerate only by proliferation of existing cells[15]. In human beings, early immunological

intervention to stop cell destruction during the development of type 1 diabetes mellitus allows

recovery of pancreatic endocrine function[16,17]. This finding might in part be attributable to

recovery in cell mass by recruitment of local pancreatic or extrapancreatic progenitor cells

that differentiate into cells and/or proliferation of remaining cells during protection from

(6)

STEM CELL THERAPY FOR COLLAGEN INDUCED ARTHRITIS (CIA)

Collagen-induced arthritis (CIA) is an animal model of rheumatoid arthritis (RA) that is

widely used to address questions of disease pathogenesis and to validate therapeutic

targets. Arthritis is normally induced in mice or rats by immunization with autologous or

heterologous type II collagen in adjuvant.

Mesenchymal stem cells (MSCs) are precursors of tissue of mesenchymal origin, but they

also have the capacity to regulate the immune response by suppressing T and B lymphocyte

proliferation in a non–major histocompatibility complex–restricted manner.

The heterogeneity of the MSC population is reflected by the absence of a unique, specific

molecular marker. MSCs derived from different tissues express developmental markers of

mesenchymal, endothelial, and hematopoietic tissues.[18-20] but they also produce molecules

directly involved in regulation of the immune response, such as the costimulatory molecule

CD28, the inhibitory molecules programmed death ligand 1(PDL-1) and PDL-2 and an array

of different cytokines[21,22]. Through these molecules, MSCs can regulate the immune

response.

A single intraperitoneal injection of allogeneic MSCs given at the moment of immunization

with CII was sufficient to prevent the occurrence of bone and cartilage erosions in the joints

of immunized mice. These are permanent, irreversible lesions corresponding to the recent

characterization of MSCs and their role in hematopoiesis and immune modulation suggests

their potential use for cell therapy most severe grade of disease and are never observed in

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engraft and survive long-term in the appropriate target organs[23], contributing to the repair of

injured tissues.[24,25] Their plasticity and capacity to undergo orthodox and unorthodox

differentiation processes allowed the use of MSCs, alone or combined with biomaterials, for

repair of tissues, such as bone[26], heart[27,28], kidney[29], lung[30,31], and brain.[32] However, in

the experiments it was found that MSC viability was not required for their long-term

immunosuppressant action; MSCs were, in fact, detectable in the recipient for no more than

10 days after treatment. During this time lag, they were able to ―educate‖ other cells to inhibit

the pathogenic immune reaction. Current therapy for RA is directed toward diminishing the

inflammatory response and treating the uncontrolled inflammation. To date, it has not been

possible to prevent the disease or to completely arrest the disease process through medical

therapy. However the research results represent an effective new therapeutic approach to

target the pathogenic mechanism of autoimmune arthritis using adult stem cells.[33]

STEM CELL THERAPY FOR CANCER

Cancer, also known as a malignant tumor or malignant neoplasm, is a group of diseases

involving abnormal cell growth with the potential to invade or spread to other parts of the

body.

Numerous studies have indicated that several human cancer types, including those of the

blood, brain, skin, lung, kidneys, gastrointestinal tract, pancreas, liver, ovarian, prostate and

testis cancers, might arise from the malignant transformation of stem cells and their

progenitors into cancer progenitor cells[34-44] .Several in vitro and in vivo studies have been

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new therapeutic targets to block the growth and/or survival of the cancer cells. Among them,

the molecular targeting of distinct oncogenic signaling elements, which are activated in the

cancer cells during the progression of numerous cancer, represents a promising strategy for

the development of new chemopreventive treatments and combination therapies against some

aggressive and metastatic cancers. The aberrant expression and/or activity of diverse

hormones, growth factors, cytokines and chemokines (androgens, estrogens, EGF and

TGF-α/EGFR, IGF/IGFR, SHH/SMO, Wnt/β-catenin, Notch, TGF-β and SDF-1/CXCR4) and

tumorigenic signaling elements (telomerase, PI3K/Akt, NF-κB and Myc-1) may contribute to

the sustained growth and survival of stem cells as well as their malignant transformation

during the initiation and cancer progression[45-50] .Therefore, their molecular targeting is of

importance to eliminate cancer progenitor cells, and thereby inducing a complete tumor

regression and cancer remission.

STEM CELL THERAPY FOR PARKINSON’S AND ALZHEIMER’S DISEASE

Parkinson's disease affects the nerve cells in the brain that produce dopamine. Parkinson's

disease symptoms include muscle rigidity, tremors, and changes in speech and gait.

Alzheimer's disease (AD), also known as Alzheimer disease, or just Alzheimer's, accounts for

60% to 70% of cases of dementia. It is a chronic neurodegenerative disease that usually starts

slowly and gets worse over time. The most common early symptom is difficulty in

remembering recent events (short-term memory loss). As the disease advances, symptoms

can include problems with language, disorientation (including easily getting lost), mood

(9)

The motor dysfunctions which are associated with Parkinson’s disease result from the

progressive loss of dopaminergic neurons in the substantia nigra pars compacta, a region of

brain that controls muscle movement. Therefore, cell replacement therapy by delivering new

dopaminergic neurons represents a putative strategy for the treatment of this

neurodegenerative disease[51-53].

A high yield of differentiation of the mouse and human ESCs into the midbrain

TH+-dopaminergic neurons has been obtained in vitro in a stromal cell-derived inducing activity

(SDIA) system or by co-culture with PA6 cells. Importantly, these neuron-like cells

expressed the specific markers of dopaminergic neurons, including the dopamine transporter,

aromatic amino acid decarboxylase, and the transcription factors associated with neuronal

and dopaminergic differentiation (Sox1, Nurr1, Ptx3 and Lmx1b). These cells were also

transplantable and a small number survived in the 6-hydroxydopamine (6-OHDA)-treated

mouse or rat striatum. In addition, Alzheimer’s disease which is characterized by regional

neuronal degeneration and synaptic loss and associated with the presence of senile plaques,

also represents a degenerative disorder that could benefit from neural cell delivery in the

(10)

CONCLUSION

Stem cells derived from all sources hold immense medical promises. Stem cell therapies have

virtually unlimited medical applications. While there are several barriers that need to be

broken down before this novel therapy can be translated from lab to clinics, it is certain that

the future is going to be exciting for all of us. We have moved on from the surgical model of

care to the medical model and are likely to move onto the biological model of care. The need

of the hour is high-quality research coupled with collaboration between basic scientists and

the clinicians for the advancement and newer approaches for this therapy. Recent

developments in the technique of stem cell isolation and expansion together with advances in

growth factor biology have set a stage for successful stem cell therapy. Stem cell therapy has

proved beneficial for genetic as well as induced disorders and find its application for treating

many diseases. Stem cell therapy has brought in a lot of optimistic hope amongst researchers,

doctors, and the patients who are the chief beneficiary of this innovation.

REFERENCES

1. http://www.eurostemcell.org/faq/what-are-stem-cells

2.

http://www.gelifesciences.com/webapp/wcs/stores/servlet/catalog/en/GELifeSciences-us/applications/types-of-stem-cells/

3. http://www.cordblood.com/benefits-cord-blood

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5. edentj.com/index.php/ijcd/article/download/895/419

6. Mehboob A Hussain, Neil D Theis Stem-cell therapy for diabetes mellitus, The Lancet,

10 July 2004; 364(9429): 203–205.

7. Bonner-Weir S, Taneja M, Weir GC, et al. In vitro cultivation of human islets from

expanded ductal tissue. Proc Natl Acad Sci USA., 2000; 97: 7999–8004.

8. Ramiya VK, Maraist M, Arfors KE, Schatz DA, Peck AB, Cornelius JG. Reversal of

insulin-dependent diabetes using islets generated in vitro from pancreatic stem cells. Nat

Med 2000; 6: 278–82.

9. Teitelman, G. Induction of beta-cell neogenesis by islet injury. Diab Metab Rev., 1996;

12: 91–102.

10.Zulewski H, Abraham EJ, Gerlach MJ, et al. Multipotential nestin-positive stem cells

isolated from adult pancreatic islets differentiate ex vivo into pancreatic endocrine,

exocrine, and hepatic phenotypes. Diabetes., 2001; 50: 521–33..

11.Lipsett M, Finegood D. Beta cells neogenesis during prolonged hyperglycemia in rats.

Diabetes., 2002; 51: 1834–41.

12.Zalzman M, Gupta S, Giri RK, et al. Reversal of hyperglycemia in mice by using human

expandable insulin-producing cells differentiated from foetal liver progenitor cells. Proc

Natl Acad Sci USA., 2003; 100: 7253–58.

13.Meivar-Levy I, Ferber S. New organs from our own tissues: liver-to-pancreas

transdifferentiation. Trends Endocrinol Metab., 2003; 14: 460–66.

14.Kojima H, Fujimiya M, Matsumura K, et al. NeuroD-betacellulin gene therapy induces

islet neogenesis in the liver and reverses diabetes in mice. Nat Med., 2003; 9: 596–603.

15.Dor Y, Brown J, Martinez OI, Melton DA. Adult pancreatic beta-cell are formed by

self-duplication rather than stem-cell differentiation. Nature., 2004; 429: 41–46.

16.Herold KC, Hagopian W, Auger JA, et al. Anti-CD3 monoclonal antibody in new-onset

type 1 diabetes mellitus. N Engl J Med., 2002; 346: 1692–98

17.Glandt M, Hagopian W, Herold KC. Treatment of type 1 diabetes with anti-CD3

monoclonal antibody. Rev Endocr Metab Disord., 2003; 4: 361.

18.Kuznetsov S, Mankani M, Gronthos S, Satomura K, Bianco P, Robey P. Circulating

skeletal stem cells. J Cell Biol., 2001; 153: 1133–9.

19.Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keenek CD, Ortiz-Gonzalez XR, et

al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature., 2002;

(12)

20.Potian JA, Aviv H, Ponzio NM, Harrison JS, Rameshwar P. Veto-like activity of

mesenchymal stem cells: functional discrimination between cellular responses to

alloantigens and recall antigens. J Immunol., 2003; 171: 3426–34.

21.Augello A, Tasso R, Negrini S, Amateis A, Indiveri F, Cancedda R, et al. Bone marrow

mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the

programmed death 1 pathway. Eur J Immunol., 2005; 35: 1482–90.

22.Liu CH, Hwang SM. Cytokine interactions in mesenchymal stem cells from cord blood.

Cytokine., 2005; 32: 270–9.

23.Allers C, Sierralta WD, Neubauer S, Rivera F, Minguell JJ, Conget PA. Dynamic of

distribution of human bone marrowderived mesenchymal stem cells after transplantation

into adult unconditioned mice. Transplantation., 2004; 78: 503–8

24.Gimeno MJ, Maneiro E, Rendal E, Ramallal M, Sanjurjo L, Blanco FJ. Cell therapy: a

therapeutic alternative to treat focal cartilage lesions. Transplant Proc., 2005; 37: 4080–3.

25.Caplan AI. Review: mesenchymal stem cells, cell-based reconstructive therapy in

orthopedics [review]. Tissue Eng., 2005; 11: 1198–211

26.Quarto R, Mastrogiacomo M, Cancedda R, Kutepov S, Mukhachev V, Lavroukov A, et

al. Repair of large bone defects with the use of autologous bone marrow stromal cells. N

Engl J Med., 2001; 344: 385–6.

27.Natsu K, Ochi M, Mochizuki Y, Hachisuka H, Yanada S, Yasunaga Y. Allogeneic bone

marrow-derived mesenchymal stromal cells promote the regeneration of injured skeletal

muscle without differentiation into myofibers. Tissue Eng., 2004; 10: 1093–112.

28.Peschle C, Condorelli G. Stem cells for cardiomyocyte regeneration: state of the art

[review]. Ann N Y Acad Sci., 2005; 1047: 376–85.

29.Kale S, Karihaloo A, Clark P, Kashgarian M, Krause D, Cantley L. Bone marrow stem

cells contribute to repair of the ischemicallyinjured renal tubule. J Clin Invest., 2003; 112:

42–9.

30.Albera C, Polak JM, Janes S, Griffiths MJ, Alison MR, Wright NA, et al. Repopulation of

human pulmonary epithelium by bone marrow cells: a potential means to promote repair.

Tissue Eng., 2005; 11: 1115–21.

31.Wang G, Bunnell BA, Painter RG, Quiniones BC, Tom S, Lanson NA Jr, et al. Adult

stem cells from bone marrow stroma differentiate into airway epithelial cells: potential

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32.Lu D, Mahmood A, Wang L, Li Y, Lu M, Chopp M. Adult bone marrow stromal cells

administered intravenously to rats after traumatic brain injury migrate into brain and

improve neurological outcome. Neuroreport., 2001; 12: 559–63.

33.Cell Therapy Using Allogeneic Bone Marrow Mesenchymal Stem Cells Prevents Tissue

Damage in Collagen-Induced Arthritis Andrea Augello,1 Roberta Tasso, 2 Simone Maria

Negrini,2 Ranieri Cancedda,3 and Giuseppina Pennesi2.

34.Modlin IM, Kidd M, Lye KD et al. Gastric stem cells: an update. Keio J Med., 2003; 52:

134-137.

35.Woodward WA, Chen MS, Behbod F et al. On mammary stem cells. J Cell Sci., 2005;

118: 3585-3594.

36.Liu S, Dontu G, Wicha MS. Mammary stem cells, self-renewal pathways, and

carcinogenesis. Breast Cancer Res., 2005; 7: 86-95.

37.Kim CF, Jackson EL, Woolfenden AE et al. Identification of bronchioalveolar stem cells

in normal lung and lung cancer. Cell., 2005; 121: 823-835

38.Mimeault M, Batra SK. Recent advances on multiple tumorigenic cascades involved in

prostatic cancer progression and targeting therapies. Carcinogenesis., 2006; 27: 1-22.

39.Fang D, Nguyen TK, Leishear K et al. A tumorigenic subpopulation with stem cell

properties in melanomas. Cancer Res., 2005; 65: 9328-9337.

40.Berns A. Stem cells for lung cancer? Cell., 2005; 121: 811-813.

41.Beachy PA, Karhadkar SS, Berman DM. Tissue repair and stem cell renewal in

carcinogenesis. Nature., 2004; 432: 324-331.

42.Wang JC, Dick JE. Cancer stem cells: lessons from leukemia. Trends Cell Biol., 2005;

15: 494-501.

43.Galderisi U, Cipollaro M, Giordano A. Stem cells and brain cancer. Cell Death Differ.,

2006; 13: 5-11.

44.Hope KJ, Jin L, Dick JE. Acute myeloid leukemia originates from a hierarchy of

leukemic stem cell classes that differ in self-renewal capacity. Nat Immunol., 2004; 5:

738-743.

45.Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature., 2005; 434: 843-850.

46.Mimeault M, Bonenfant D, Batra SK. New advances on the functions of epidermal

growth factor receptor and ceramides in skin cell differentiation, disorders and cancers.

Skin Pharmacol Physiol., 2005; 17: 153-166. www.StemCells.com at Stanford University

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47.Mimeault M, Brand RE, Sasson AA et al. Recent advances on the molecular mechanisms

involved in pancreatic cancer progression and therapies. Pancreas., 2005; 31: 301-316

48.Murphy MJ, Wilson A, Trumpp A. More than just proliferation: Myc function in stem

cells. Trends Cell Biol., 2005; 15: 128-137.

49.Kubo M, Nakamura M, Tasaki A et al. Hedgehog signaling pathway is a new therapeutic

target for patients with breast cancer. Cancer Res., 2004; 64: 6071-6074.

50.Romer J, Curran T. Targeting medulloblastoma: small-molecule inhibitors of the Sonic

Hedgehog pathway as potential cancer therapeutics. Cancer Res., 2005; 65: 4975-4978

51.Lindvall O, Kokaia Z, Martinez-Serrano A. Stem cell therapy for human

neurodegenerative disorders-how to make it work. Nat Med., 2004; 10: S42-S50.

52.Zeng X, Cai J, Chen J et al. Dopaminergic differentiation of human embryonic stem cells.

Stem Cells., 2004; 22: 925-940.

53.Correia AS, Anisimov SV, Li JY et al. Stem cell-based therapy for Parkinson’s disease.

Ann Med., 2005; 37: 487-498.

54.Recent Advances on the Significance of Stem Cells in Tissue Regeneration and Cancer

Therapies Stem Cellspublished online Jun 22, 2006; Murielle Mimeault and Surinder K.

References

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